antiepileptic drug therapy: role of newer agents - Pakistan Journal Of ...

Epilepsy is a common neurological disorder with an
estimated worldwide prevalence of approximately 1%. It is
also a chronic, at times debilitating illness and carries with
it an increased incidence of accidental injuries, psychiatric
diseases as well as sudden death. 1 Early recognition and
treatment is therefore of critical importance in reducing
morbidity and mortality associated with the disease.
Appropriate antiepileptic therapy effectively controls
seizures in approximately 60-75% of cases, either as
monotherapy or as combination therapy. 2 , 3 Treatment of
epilepsy is also important in improving the quality of life in
patients with epilepsy and is frequently effective in treating
co-existing disorders such as bipolar disease, neuropathic
pain and migraine. 4
Prior to 1990, only a handful of antiepileptic drugs (AEDs)
were available for the treatment of epilepsy. These
included phenytoin, carbamazepine, phenobarbital,
primidone, and divalproex sodium, also known as the
“older” antiepileptic agents. A number of agents have
been approved by the Food and Drug Administration in the
United States (and elsewhere in the world) since 1990
and are referred to as the “new AEDs” (Table 1).
Interestingly, a number of these new agents (such as
gabapentin and tiagabine) have shown limited utility or
have been associated with serious adverse effects
(vigabatrin and felbamate). 5 Brief information regarding
dosing and adverse effects of these new AEDs is listed in
Tables 2 and 3, respectively.
P A K I S T A N J O U R N A L O F N E U R O L O G I C A L S C I E N C E S 223
Issues in C L I N I C A L P R A C T I C E
ANTIEPILEPTIC DRUG THERAPY: ROLE OF NEWER
AGENTS
Imran I Ali
Department of Neurology, University of Toledo College of Medicine, Toledo, Ohio, United States
Correpondence to: Dr. Ali, Professor of Neurology, University of Toledo College of Medicine, 3000 Arlington Avenue, MS 1195, Toledo, Ohio 43614, USA
Email: imran.ali@utoledo.edu
Pak J Neurol Sci 2007; 2(4): 223-29
TABLE 1
New Antiepileptic Drugs
Felbamate
Gabapentin
Lamotrigine
Levetiracetam
Pregabalin
Tiagabine
Topiramate
Zonisamide
This review aims to focus on the currently utilized AEDs
with demonstrable efficacy and tolerability and will
summarize the current approach to medical management
of epilepsy.
FELBAMATE
Felbamate was one of the first newer generation AEDs
approved in the USA. The mechanism of action is related
to NMDA antagonism, modulation of GABA and glycine
receptors, as well as inhibition of sodium channels. It is
effective in the treatment of partial seizures as well as
Lennox-Gastaut Syndrome (LGS), a refractory form of
secondary generalized epilepsy. 6,7 In a study of LGS with
felbamate, there was a substantial decline in the
frequency of atonic and tonic-clonic seizures. 6 S i m i l a r l y ,
patients with partial epilepsy had a statistically significant
decline in the number of seizures compared with
placebo. 7
However, within a few years of felbamate's approval, fatal
aplastic anemia as well as hepatic failure were reported at
a greater than expected rate. Although FDA did not pull it
off the market, its use is now limited to the extremely
refractory cases of epilepsy that are not amenable to
surgical therapy and remain unresponsive to all other
available agents. Patients requiring treatment with
felbamate need to be informed of the potential risks of
these fatal complications. The reported risk of hepatic
failure with felbamate is 1 in 26-30,000, while the risk of
aplastic anemia is 27-209 cases per million. Most of
these complications occurred in the first year of treatment
with felbamate; therefore, greater vigilance is required
during this period.
It is recommended that a complete blood count and liver
function profile be obtained frequently during the first year
and periodically afterwards. There is no evidence that this
monitoring alone will pick up development of felbamateinduced
toxicity in the absence of good clinical oversight.
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TABLE 2
Dosages of the new antiepileptic drugs
Antiepileptic drug Initial dose Maintenance daily dose
Felbamate 300 mg bid (adults) 2400-3600 mg Two or three divided doses
15 mg/kg/day (pediatrics) 45 mg/kg/day
Gabapentin 300 mg tid (adults) 900-3600 mg (adults) Three divided doses
10-15 mg/kg (pediatrics) 25-60 mg/kg (pediatrics)
Levetiracetam 500 mg bid (adults) 1000-3000 mg Two divided doses
10-20 mg/kg/day (pediatrics) 60 mg/kg/day
IV formulation available
(same dose as oral)
Topiramate 25 mg bid (adults) 100-400 mg (adults) Two divided doses
1-3 mg/kg/day (pediatrics) 5-9 mg/kg/day (pediatrics)
Lamotrigine* 25 mg bid with EI^ AED,
25 mg qod with VPA (adults) 200-600 mg with EI AED,
100-300 mg with VPA (adults)
0.6 mg/kg/day with EI AED, 5-15 mg/kg/day with EI AED,
0.1 mg/kg/day with VPA # 1-5 mg/kg/day with VPA (pediatrics)
(pediatrics)
Zonisamide 100 mg qd (adult) 200-600 mg (adults) Single daily dose
2-4 mg/kg (pediatrics) 4-8 mg/kg (pediatrics)
Oxcarbazepine 300 mg bid (adult) 1200-2400 mg (adults) Two divided doses
8-10 mg/kg (pediatrics) 20-50 mg/kg
Tiagabine 4 mg/day (adult) 32-64 mg Three to four divided doses
Pediatric dosing not established
Pregabalin 25-50 mg bid or tid 200-300 mg Two to three divided doses
*Consult prescribing guidelines for detailed information including use with “neutral” (non-enzyme inducing or inhibiting) AEDs. ^EI - enzyme-inducing.
# VPA - valproic acid.
GABAPENTIN
Gabapentin is a novel AED which was developed as a
GABA agonist but at present this is not considered its
primary mechanism of action. Recently, an inhibitory
effect on the _2 _ receptor subunit of the calcium channel
has been shown and postulated to be responsible for its
antiepileptic effect. 8 Gabapentin is approved for the
treatment of partial seizures only and may exacerbate
absence seizures. This drug differs from other AEDs as it is
absorbed through an L-amino acid transporter and has
almost linear pharmacokinetics. It is renally excreted and
the dose needs to be adjusted in patients with renal
insufficiency.
Post-marketing experience suggests that gabapentin is
well tolerated at lower doses but seems to have lesser
efficacy than some of the other newer generation AEDs. It
is on some occasions used as monotherapy in elderly
patients with infrequent seizures as well as those with
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complex medical illnesses, as it lacks drug-drug
interactions and systemic side effects. Although
considered not to have major side effects, some patients
do develop dizziness, somnolence, weight gain and
peripheral edema.
LAMOTRIGINE
Lamotrigine is a well established AED with proven efficacy
in partial as well as generalized epilepsy. 9 L a m o t r i g i n e
acts by use- and voltage-dependant blockade of neuronal
voltage-activated sodium channel, like phenytoin and
carbamazepine. It is perhaps the most well studied of the
newer agents, showing efficacy in partial and generalized
epilepsy, both in children and adults. 1 0 , 1 1 Lamotrigine is
also approved by the FDA for use as monotherapy in
patients with partial seizures. It is effective in the
treatment of Idiopathic Generalized Epilepsy (IGE)
syndromes such as absence and juvenile myoclonic
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TABLE 3
Adverse effects of the new antiepileptic drugs
Antiepileptic drug Common adverse effects Serious adverse effects
Felbamate Insomnia, nausea, weight loss Hepatic failure, aplastic anemia
Gabapentin Dizziness, weight gain, fatigue, peripheral edema None reported
Levetiracetam Dizziness, fatigue, confusion, somnolence Irritability, psychosis
Topiramate Lethargy, dysphasia, confusion, distal paresthesiae, weight loss Renal stones, glaucoma (rare)
Lamotrigine Insomnia, restlessness, headaches, diplopia Rash leading to SJS
Zonisamide Somnolence, dizziness, anorexia, weight loss Rash, renal stones, blood dyscrasias,
hepatotoxicity
Oxcarbazepine Sedation, dizziness, nausea, diplopia Hyponatremia, rash, hepatotoxicity
Tiagabine Sedation, impaired cognition Rare cases of status epilepticus
Pregabalin Sedation, weight gain, dizziness, thrombocytopenia, Renal tumors in certain animals,
diplopia edema
epilepsy (JME), but rare cases of exacerbation of
myoclonus in progressive myoclonic epilepsy (PME) have
also been reported. 1 2 Patients with PME treated with
lamotrigine should be carefully observed for exacerbation
of myoclonus.
In our experience as well, lamotrigine is effective as a
broad spectrum drug and can be used in both partial
onset and generalized epilepsies. Positive mood effects,
lack of significant central nervous system side effects and
reasonable safety profile makes it an attractive option as a
first-line agent for most patients with epilepsy. 13,14 There
are, however, some issues of clinical significance
associated with this drug. There is an increased incidence
of rash sometimes seen with rapid titration that does not
follow the recommended guidelines. The rash may rarely
lead to development of Stevens Johnson Syndrome (SJS)
or toxic epidermal necrolysis (TEN). Fortunately, the
incidence of rash (5-10%) has decreased since the dosing
guidelines have been modified and the incidence of
SJS/TEN is now reported to be less than 1% in most
studies. 15
Lamotrigine undergoes metabolic breakdown in the liver
and is inhibited by divalproex sodium and sertraline.
Lamotrigine levels are lowered by concomitant use of
phenytoin, carbamazepine, and Phenobarbital, as well as
estrogen-containing contraceptives. Since lamotrigine
levels are lowered significantly by estrogens, it has the
potential to lead to breakthrough seizures. Lamotrigine
dosages may need to be increased in patients during the
“estrogen” phase and lowered afterwards to avoid toxicity.
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Lamotrigine itself has negligible effects on serum levels of
most medications. A 30 % reduction in estrogen levels of
oral contraceptives has been noted but at present there
are no reports of contraceptive failure with this agent
(Table 4). 16
TABLE 4
New antiepileptic drugs affecting oral contraceptives
Oxcarbazepine
Topiramate (dose 200 mg/day or >)
Lamotrigine (significance unknown)
One of the most important advantages of lamotrigine is
related to its low incidence of teratogenicity in women with
e p i l e p s y . 1 4 , 1 7 Current analysis of retrospective data
suggests that the incidence of major malformations is
approximately 2-3% at doses of 200 mg per day or less,
which is similar to that of the control population. Some
concerns have been raised recently regarding an
increased incidence of cleft lip in off-springs of women
taking lamotrigine. The number of cases is quite small so
far, so no firm conclusions can be drawn at this time.
However, prior to any categorical and definitive
conclusions regarding its safety in pregnancy can be
made, it is recommended that patients should be
informed of potential risks and benefits of therapy.
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In summary, Lamotrigine appears to be a very effective
AED in patients with new onset and refractory epilepsy in
both pediatric and adult age groups, with limited adverse
effects noted in randomized and controlled studies as well
as based on post-marketing experience. Studies have also
shown efficacy and remarkable tolerability in elderly
patients with epilepsy. 1 8 Lamotrigine is also effective for
treatment of bipolar disorder and the mood-stabilizing
effects are sometimes evident in patients being treated for
epilepsy with this agent.
LEVETIRACETAM
Levetiracetam is a truly novel antiepileptic because it
binds to a hitherto previously unknown target for AEDs.
Studies have shown its antiepileptic effects are related to
binding of a synaptic vesicle protein SV2A. 1 9
Levetiracetam does not undergo extensive metabolism in
the body and is renally excreted, so the dose may need to
be adjusted in renal failure. It is an effective adjunctive
treatment option for patients with partial epilepsy. 2 0
Recent studies have shown efficacy in idiopathic
generalized epilepsy with and without myoclonus as
well. 21 Since an intravenous formulation was introduced,
there have been case reports of its role in hospitalized
patients with seizures as well as for patients with acute
repetitive seizures. As yet, no evidence has been found to
suggest a role in early treatment of status epilepticus;
however, anecdotal reports have suggested possible
benefits in myoclonus associated with hypoxic-ischemic
encephalopathy as well as in the treatment of nonconvulsive
status epilepticus.
Due to lack of any drug interactions and significant
systemic side effects, levetiracetam is useful in patients
with complex medical problems, as well as those requiring
rapid titration of an AED. Intravenous loading with 1000-
2000 mg usually does not produce any significant
respiratory suppression, which is a distinct advantage in a
patient with frequent seizures. In approximately 10-20% of
patients treated with levetiracetam, somnolence,
irritability, behavioral changes as well as marked
exacerbation of underlying psychiatric disease has been
noted. 23 In our experience, this does not appear to be a
dose-related phenomenon and occurs early during
treatment. Overall, this drug appears to be an effective
agent for both partial and generalized epilepsy with limited
drug interactions and favorable pharmacokinetics.
OXCARBAZEPINE
Oxcarbazepine was developed as an agent with a profile
similar to carbamazepine. Due to absence of the epoxide
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metabolite, it was assumed that oxcarbazepine would
have fewer adverse effects. However, oxcarbazepine has
its own set of issues and has not replaced carbamazepine
as a primary agent for the treatment of partial seizures.
Oxcarbazepine has a similar mechanism of action to
carbamazepine, although unlike carbamazepine, it
appears to have some inhibitory effects on potassium and
calcium channels as well. Oxcarbazepine is approved for
treatment of partial seizures in pediatric and adult age
groups. It is an effective antiepileptic drug as monotherapy
as well as adjunctive therapy for partial seizures. Although
there are pharmacological similarities to carbamazepine, it
is effective even in patients who have failed
carbamazepine. Most of the evidence suggests that it is a
significantly different drug compared with carbamazepine -
based on efficacy, adverse effects, safety and tolerability.
Interestingly, the side effects in our experience appear to
be at par or at times greater than with carbamazepine.
Hyponatremia is a particularly frequent problem; it is
extremely uncommon in children but the risk increases
with age and almost a third of patients above the age of
65 may develop this complication. 25 Other common side
effects including rash, dizziness, diplopia, fatigue, as well
as weight gain.
Oxcarbazepine also induces estrogen metabolism and may
lead to oral contraceptive failure. Teratogenicity data at
present shows conflicting results and the number of
patients on monotherapy who have been pregnant has not
reached statistical significance for any conclusions to be
drawn at this time.
PREGABALIN
Pregabalin is a recent addition to the list of AEDs available
for treatment of epilepsy. Like gabapentin, it binds to the
alpha2-delta subunit of the calcium channel, modulating
use-dependant neuronal activity. Pregabalin is effective for
treatment of partial epilepsy as an adjunctive agent and
has also been shown to be effective in treatment of
diabetic neuropathy and post-herpetic neuralgia. 2 6
Pregabalin has anxiolytic properties that make it an
attractive option in approximately 3-10% of patients with
epilepsy who may have an underlying anxiety disorder or
anxiety secondary to their epilepsy.
Robust efficacy data in partial epilepsy is somewhat
tempered by an increased incidence of side effects that
appear to be dose-related. These include dizziness,
confusion, ataxia and somnolence. Substantial weight gain
has also been seen in patients with increasing dose. Rare
cases of hypersensitivity including idiosyncratic laryngeal
swelling have been noted as well.
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TIAGABINE
Tiagabine is a selective GABA reuptake blocker and is
useful as an adjunctive agent in the treatment of partial
epilepsy. It has limited use due to multiple daily, dosing
requirements, significant CNS adverse events including
exacerbation of depression, and behavioral problems as
well as rare cases of development of non-convulsive status
e p i l e p t i c u s . 2 7 Tiagabine remains an option for patients
with refractory epilepsy and those with poor response to
other first or second line AEDs.
TOPIRAMATE
Topiramate is also a broad spectrum AED with multiple
mechanisms of action including inhibitory effects on
sodium and calcium channels as well as the kainate
subgroup of glutamate receptors. Additionally, it
potentiates effects on GABA receptors as well as on the
potassium channel. It is also a partial carbonic anhydrase
inhibitor, although this effect is weak and probably of little
consequence in relation to its efficacy but appears to be
associated with some of the known side effects such as
paresthesias, metabolic acidosis and urolithiasis. There is
excellent efficacy data regarding topiramate in partial
epilepsy in children and adults, as monotherapy as well as
adjunctive therapy. 2 8 A number of studies have also
shown statistically significant reduction in seizures in
idiopathic generalized epilepsy. 29
Topiramate has also been shown to be effective in
prevention of migraine headaches. 2 9 Major side effects
include cognitive impairment, weight loss, urolithiasis as
well as somnolence. Some of these effects may be doserelated
and more likely to occur above 200 mg per day.
Reduction in oral contraceptive efficacy is noted at this
dose as well.
ZONISAMIDE
Zonisamide is structurally related to other sulfa derivatives
and functionally shares some of the features associated
with topiramate. It has an inhibitory effect on both sodium
and calcium channels. It is effective in treatment of partial
epilepsy but efficacy has also been shown in some forms
of generalized epilepsy such as JME and PME. 3 0 - 3 2
Zonisamide is effective as adjunctive therapy in patients
with partial epilepsy and is also used as a second or third
line alternative in refractory generalized epilepsy. Side
effects include a hypersensitivity rash, somnolence,
irritability, mood disorder and renal stones. Like
topiramate, it is a weak carbonic anhydrase inhibitor and
may lead to anhydrosis and possibly heat shock. Due to its
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presumed effects on dopaminergic pathways, there has
been some interest in treating Parkinson's disease with
zonisamide as well. 33
SELECTING AN APPROPRIATE ANTIEPILEPTIC DRUG
The presence of additional AEDs has certainly given
physicians a variety of different options for treatment of
new and established patients with epilepsy. This
availability of additional agents has not necessarily had a
significant impact on the number of patients rendered
seizure free. However, what it has allowed one to do is
match a specific drug to a specific patient. Patients with
epilepsy and their health care providers now have an
option to choose an appropriate AED based on the
spectrum of activity, side effect profile as well as efficacy
in other concomitant disease states. Therefore, important
issues to consider while selecting a specific AED are not
only the type of epilepsy but also associated
comorbidities, side effect profile, cost, and probability of
compliance. As an example, a young obese man with new
onset partial seizures and migraine headaches may benefit
more from topiramate as monotherapy rather than
carbamazepine. Topiramate in this case may also result in
reduction in frequency of headaches and weight loss may
be a welcome side effect.
APPROACH TO A PATIENT WITH PARTIAL EPILEPSY
In a patient diagnosed with partial epilepsy the choice of
AED may vary based on a number of factors elucidated
above. In young adults, lamotrigine is an excellent option
both as initial and adjunctive therapy as it has minimal
cognitive side effects and is extremely well tolerated by
most patients. Lack of significant teratogenicity makes it a
reasonable first choice in women of child bearing age.
Additionally oxcarbazepine and topiramate are other
agents that can be used as first line or as adjunctive
therapy for partial epilepsy. Levetiracetam and pregabalin
are reasonable alternatives as adjunctive therapy. In our
experience, levetiracetam is a better adjunctive therapy
option in some patients as it has no significant drug-drug
interactions and is well tolerated in most cases.
Approximately 15-20% of patients may develop behavioral
problems and the drug should be discontinued in those
patients. It can be used as monotherapy in some patients
as well. Pregabalin has added advantage of being effective
for treatment of neuropathic pain but side effects may
limit its use in some patients. Zonisamide is an option for
patients with both partial and generalized epilepsy.
Tiagabine use is limited to third or fourth line in patients
with partial epilepsy for the reasons discussed above.
Felbamate is clearly reserved for patients with refractory
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epilepsy who have not responded to other AEDs and are
not considered appropriate surgical candidates. The
benefits in these cases need to far outweigh the risks.
A sizable number of newly diagnosed cases of seizures are
now in the elderly population that is inherently more
susceptible to adverse cognitive effects of AEDs and may
be more likely to be harmed by drugs with significant
pharmacokinetic interactions. There have been a number
of studies comparing carbamazepine, gabapentin and
lamotrigine in the elderly, all of them suggest equal
efficacy but greater tolerability with lamotrigine, a result
that is not too surprising based on our experience and
that of others. 18
APPROACH TO A PATIENT WITH GENERALIZED
EPILEPSY
In a patient with idiopathic generalized epilepsy divalproex
sodium remains the drug of choice. Due to considerable
side effects with this drug including weight gain,
hepatotoxicity, thrombocytopenia, osteomalacia and
tremors, alternative agents are frequently required. Data
from randomized, controlled trials have shown that
lamotrigine and topiramate are reasonable alternatives in
patients with absence, myoclonic as well as generalized
tonic-clonic seizures. A recent study has shown that
levetiracetam reduces frequency of generalized and
myoclonic seizures in IGE as well. 2 1 Zonisamide is an
additional option for this type of epilepsy.
In patients with secondary generalized epilepsy, such as
LGS, randomized, controlled trials have shown that
topiramate, lamotrigine and felbamate are also effective
as adjunctive therapy and considerable date supports
their use in this type of epilepsy.
It should be noted that drugs such as gabapentin,
tiagabine and oxcarbazepine may exacerbate seizures in
generalized epilepsies and should be avoided.
ANTIEPILEPTIC AGENTS IN DEVELOPMENT
A number of novel AEDs are in different phases of
d e v e l o p m e n t . 3 4 Brivaracetam is a structural analogue of
levetiracetam; preliminary data suggests that is more
potent and effective in treatment of both partial and
generalized epilepsy with minimal tolerability issues.
Another new AED currently in review by FDA for approval is
lacosamide. Early data from randomized controlled trials
would suggest robust efficacy in partial seizures. An added
benefit appears to be availability of an intravenous
formulation as well as efficacy in treatment of neuropathic
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pain. Rufinamide is also currently in Phase III trials for
treatment of partial seizures. It has been shown to have
significant efficacy in patients with LGS; however the
present data shows only modest benefits in partial
epilepsy. Retigabine is a novel AED which activates a
specific type of potassium channel (KCNQ2/3). In two
randomized clinical trials it has demonstrated dose-related
efficacy for treatment of partial seizures as an adjunctive
agent. Numerous other agents are also currently in
development and the reader is referred to a recent review
for more detailed information. 34
SUMMARY
There are currently multiple new AEDs available for
treatment of epilepsy. Their role in treatment of individual
patients requires a thorough understanding of the
pharmacological characteristics of these agents as well as
that of the underlying epilepsy syndrome. Careful
matching of the drug to the patient may not only control
epilepsy but may also improve the quality of life of that
individual, which should be the ultimate goal.
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